Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Papp, R; Nagaraj, C; Zabini, D; Nagy, BM; Lengyel, M; Skofic Maurer, D; Sharma, N; Egemnazarov, B; Kovacs, G; Kwapiszewska, G; Marsh, LM; Hrzenjak, A; Höfler, G; Didiasova, M; Wygrecka, M; Sievers, LK; Szucs, P; Enyedi, P; Ghanim, B; Klepetko, W; Olschewski, H; Olschewski, A.
Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension.
Eur Respir J. 2019; 53(6): 1800965
Doi: 10.1183/13993003.00965-2018
Web of Science
PubMed
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- Leading authors Med Uni Graz
- Olschewski Andrea
- Papp Rita
- Co-authors Med Uni Graz
- Chandran Nagaraj
- Egemnazarov Bakytbek
- Höfler Gerald
- Hrzenjak Andelko
- Kovacs Gabor
- Kwapiszewska-Marsh Grazyna
- Marsh Leigh
- Nagy Miklos Bence
- Olschewski Horst
- Sharma Neha
- Zabini Diana
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- Abstract:
- Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl- channel TMEM16A gene. We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing pulmonary arterial hypertension (PAH).We investigated healthy donor lungs (n=40) and recipient lungs with IPAH (n=38) for the expression of anion channel and transporter genes in small pulmonary arteries and pulmonary artery smooth muscle cells (PASMCs).In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl- current in PASMCs (n=9-10). These cells were depolarised and could be repolarised by TMEM16A inhibitors or knock-down experiments (n=6-10). Inhibition/knock-down of TMEM16A reduced the proliferation of IPAH-PASMCs (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMCs produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established pulmonary hypertension.Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying the vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to reverse remodelling in PAH. Copyright ©ERS 2019.